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Striking a responsive cord

By Nicolas CurrierAssociate Medical Director, Clinical Science

April 25, 2017

The lining of the blood vessels that feed the central nervous system (CNS) are like the world’s toughest border patrol: There is just no way that most molecules can get past these cells into nerves.

But there’s another route to administer medicines to the CNS, via cerebrospinal fluid (CSF), which bathes both the brain and the spine. Our research group studies ways to help improve this delivery.

Doctors can inject medicines directly into the CSF in a procedure known as a lumbar puncture. Working as a pediatric oncologist before coming to Biogen, I frequently performed this procedure to administer chemotherapies. The technique, which also can deliver pain medications, employs a precisely positioned small needle to inject the medicine in an area safely below the spinal cord.

This is the way that Biogen’s nusinersen, which was approved by the Food and Drug Administration in December 2016 to treat the rare genetic disease of spinal muscle atrophy (SMA), is administered. Nusinersen is an “antisense oligonucleotide” (ASO) therapy, using modified RNA to boost production of a key protein called SMN that is deficient in SMA.

Our group looks to advance our understanding of how ASO molecules are delivered to neurons via the CSF, and to optimize their delivery.

Fluid measurements
Surprisingly enough, what happens to a medicine that enters the CSF is only known in a fairly rudimentary manner. We only partially understand, for example, how best to keep a drug in the spinal cord area or to deliver it to other parts of the brain. The answer may be a bit different for each medicine delivered into the CSF.

One key goal for our group is to accurately understand the volume of the CSF surrounding the spinal cord and brain, which is a particularly important parameter when trying to model the distribution of ASOs in the CSF. We’re putting a medicine into a pond of fluid, so how big is that pond?

Magnetic resonance imaging (MRI), which can light up the CSF very clearly, will help us answer this question. We’re examining existing MRI databases from healthy children and adults as well as collecting new MRIs from children with CNS diseases – all to better understand the volumes of CSF in various patients.

Getting the nerve
Even more than how a medicine moves in the CSF, though, we want to follow the medicine into the cells it targets.

In the case of SMA, the target cells are motor neurons. These are particularly difficult to study because we can’t, of course, take samples from patients. The best we can do now is to assess the disappearance of the medicine from the CSF and try to correlate that with our knowledge of how the medicine behaves in preclinical models.

We want a way to label ASO drug candidates and watch their behavior in people. We’re working on researching ways to do this with SPECT (single-photon emission computed tomography), putting a radioactive tag on the drug candidate so that we can watch how it distributes throughout the CSF and tissues. That’s our dream scenario, and reaching it brings all the challenges of developing a test that subjects people to radiation.

We’re currently developing a testing tool and designing experiments with the hope that the tool can be safe and informative. Our plan then is to study it with a suitable drug clinical candidate.

As we understand more about how ASOs move through the body, we can research new opportunities to help optimize them. We hope to find ways to help lower the doses and the frequency of dosing for ASO therapies and a range of promising clinical candidates for CNS diseases.

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